ABSTRACT Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disease. How neurons are lost in AD brains remains contested, although many studies have postulated that toxic ?-amyloid peptide (A?) in various forms (such as soluble multimers or oligomers) as well as tau aggregates contribute to neuronal loss in aging AD brains and synaptic dysfunction in AD patients. AD mouse models such as PS19 and 5XFAD do develop age-dependent neurogeneration, supporting the above assertion. Currently, AD therapy is centered on developing drugs to block or remove amyloid deposition or tau aggregation. In this proposal, we aim to investigate how to revert neuronal loss in AD brains as an alternative therapeutic strategy by reversing degenerative processes. We have recently discovered that mice overexpressing either full-length CX3CL1 (Tg-CX3CL1) or the C-terminal domain of CX3CL1 (Tg-CX3CL1-ct) show enhanced neurogenesis. CX3CL1, which is also known as fractalkine, is a type I transmembrane chemokine (Bazan et al., 1997;Pan et al., 1997) and is cleaved by ADAM10 (Hurst et al., 2012;Hundhausen et al., 2003) to release its N-terminal fragment containing the C-XXX-C motif, which mediates binding to the G protein-coupled CX3CR1 receptor (Imai et al., 1997). Since the discovery of CX3CL1, its biological functions have exclusively been shown to occur through CX3CL1/CX3CR1 interactions, which activate signal transduction to regulate inflammatory responses, leukocyte capture and infiltration, as well as other immune functions. However, we have discovered that the C- terminal domain has a back-signaling function, which regulates the expression of genes important for cell growth or differentiation. We aim to test the hypothesis that neuronal expression of CX3CL1 enhances neurogenesis through its C-terminal domain, which replenishes neuronal loss and fosters recovery of synaptic functions in AD mouse models. Three specific aims are proposed to test this hypothesis: Aim 1: To determine the role of CX3CL1 C-terminal domain (CX3CL1-ct) in the control of neurogenesis; Aim 2: To enhance neurogenesis to reverse impaired synaptic functions in AD mouse models; and Aim 3: To explore potential therapeutic use of CX3CL1-ct in age-dependent neurogenesis for AD therapy. Accomplishing the experiments as proposed will provide novel answers as to the translational potential of CX3CL1 in AD treatment. Knowledge gained from this study will guide future development of molecules targeted as an AD combinatorial therapy that will not only reducing amyloid deposition or tau aggregation, but will also replenish neurons.